Learning Objectives
1) Explain the epidemiology and prevalence of Wilson’s Disease
2) Describe the typical presentation of Wilson’s Disease
3) Describe the prognosis and treatment for Wilson’s Disease
4) Name the genes involved and mode of inheritance for Wilson’s Disease
5) Name and describe the variations of Wilson’s Disease
6) Create a genetic counseling plan for a patient and the family members of
a person with Wilson’s Disease
Pretest Questions
1) Of which of the following ages do almost 100% of patients with Wilson’s
Disease present?
a.) 15
b.) 10
c.) 30
d.) 45
e.) 55
2) The first majority of patients with Wilson’s Disease present with
which symptom?
a) chronic hepatitis
b) neuropsychiatric disease
c) fulminant hepatic failure
d) cardiac arythmia
e) Arthropathy
3) Through what mode of inheritance is Wilson’s Disease acquired?
a) autosomal dominant
b) autosomal recessive
c) x-linked
d) incomplete penetrance
e) multivariant inheritance
4) Liver biopsy results of patients with Wilson’s Disease is sometimes
misinterpreted and incorrectly treated as which of the following diseases?
a) Hemochromatosis
b) Hepatoblastoma
c) Autoimmune Hepatitis
d) Duodenal Ampullary Carcinoma
e) Colorectal Carcinoma Mets
5. Which of the following genes plays a role in the development of Wilson’s
Disease?
a) ApoA2
b) BA4
c) ApoE4
d) ATP7B
e) APC
Answers: 1) c 2) a 3) b 4) c 5) d
Case Study
A 27 year old male is referred to GI clinic for evaluation of increased serum
aminotransferase and bilirubin. Lab tests revealed negative Hepatitis A, B,
and C serology. The patient denies alcohol or drug use of any kind. The patient
has noticed a decrease in his ability to concentrate during his graduate school
courses over the last year, but he has attributed this as a result of stress
while trying to obtain his PhD. A liver biopsy is suggestive of an auto-immune
hepatitis picture. However, both original and repeat lab results of ANA titers
is negative. The patient denies fevers, chills, nausea, vomiting, gastro-esophageal
reflux, hematemesis, melena, weight loss, diarrhea, constipation, or a change
in bowel habits. Family history is non-contributory. Physical exam is unremarkable.
What additional lab tests should be ordered?
Explain the epidemiology and prevalence of Wilson’s Disease:
Wilson’s disease occurs in approximately 1 in 30,000 live births. A defect
causing a decrease in biliary excretion and a decrease in formation and secretion
of ceruloplasmin results in decreased copper elimination from the liver. This
accumulation of copper progressively damages the organ until it becomes cirrhotic.
Once cirrhosis occurs, copper will leak into the plasma and eventually damage
other tissues and organs. Patients rarely present with the disease before 6
years of age, but almost 100% of patients will be diagnosed by the age of thirty.
What is the typical presentation of Wilson’s Disease?
Younger patients usually present with liver disease while those who are first diagnosed
at slightly older ages (20’s and 30’s) often present with neuropsychiatric disease. The
following are a list of presenting manifestations of patients with Wilson’s Disease:
1) Hepatic
Disease
a)
Chronic Hepatitis- 40% of patients present with signs of hepatocellular disease
such as chronic hepatitis or cirrhosis. Pathological findings are often
similar to autoimmune hepatitis. Physicians should be careful not to incorrectly
treat these patients with corticosteroids.
2) Portal
Hypertension
-Rarely,
patients will present with splenomegaly, leukopenia, and thrombocytopenia,
all signs of advanced portal hypertension
3) Fulminant
Hepatic Failure
-children
and young adults sometimes present with hemolytic anemia, hemoglobinuria,
dark urine, and renal failure as a result of the hepatocellular
necrosis. These patients are in urgent need for liver transplantation.
In order to temporarily stabilize the patient, plasma exchange
with fresh frozen plasma can be performed.
4) Asymptomatic
Liver Function Abnormalities
-lab
abnormalitites sometimes serve as the only indication of disease. Usually
increased serum aminotransferase and bilirubin concentrations are observed.
5) Liver
Biopsy
-findings
are often similar to nonalcoholic steatohepatitis and autoimmune hepatitis.
Early findings include: glycogen inclusions within nuclei, fatty infiltration
within hepatocytes, and portal fibrosis. Copper stains have limited
sensitivity but can be suggestive of Wilson’s Disease.
6) Other
Lab Findings
-Serum
ceruloplasmin concentration- the majority of patients will have low
serum ceruloplamsin levels. This finding alone is not adequate for diagnosis
of Wilson’s disease and usually needs a 24 hour urinary copper excretion
to confirm the diagnosis. However, in a patient with Kayser- Fleishcer
rings, a concentration less than 20 mg/dL confirms the diagnosis.
-Serum
copper concentration-the majority of patients will have low serum
copper concentrations despite a high total copper body stores.
-Urinary
Copper Excretion-when 24 hour excretion of copper is equal or greater
than 100mcg, a diagnosis of Wilson’s disease can be confirmed. However,
25% of patients may have lower excretion rates, especially
in pre-symptomatic
patients. Patients with a copper excretion of > 40 mcg should
undergo a liver biopsy to confirm the diagnosis. -Penicillamine
Challenge- To increase specificity, Wilson’s Disease can be
confirmed by administrating a one initial 500 mg dose and a second dose
again at 12 hours during a 24 hour copper collection.
7) Neuropsychiatric
Disease
-35%
of patients present with neuropsychiatric symptoms. Patients present
with uncoordinated gait, speech slurring, risus sardonicus, drooling,
and a Parkinsonian-like tremor. Upon further investigation, asymptomatic
hepatic involvement is usually present. CSF fluid will have
a copper concentration 3-4 times higher than in Wilson’s disease patients
with no neurological involvement. These levels usually fall with appropriate
treatment.
-10%
of patients present with more subtle personality changes such as: depression,
decrease in school performance, paranoia, and catatonia.
8) Other
Clinical Manifestations:
a)
Kayser-Fleischer rings- detectable by slit-lamp exam. They are gray- green
rings present in the inferior and superior poles of the cornea.
b)
Sunflower Cataracts-copper deposits in the lens of the eye
b)
Fanconi’s Syndrome- proximal renal tubular acidosis causes glucosuria, aminoaciduria,
and hypouricemia.
c)
Arthropathy- premature arthritis, chondrocalcinosis, usually located in the
knee
d)
Cardiac arrythmia
e)
Impotence
What is the prognosis and treatment for Wilson’s Disease?
Treatment is most effective when applied to patients early
in the disease course. As a result, the prognosis continues to be excellent
in all but the most advanced patients with Wilson’s disease. Individuals
require lifetime treatment. Treatment involves both removal of tissue in which
copper has accumulated as well as preventing further accumulation. D-penicillamine
is a potent chelator most often used for copper removal. There is a significant
side-effect profile of the medication in up to 30% of patients, especially
those with neurological symptoms. As a result, trientine is used as a second-line
agent. Further treatment involves either low dose chelators or zinc in order
to prevent the re-accumulation of copper in tissues. Patients should also be
advised to avoid high copper-containing foods such as: kidney, liver, shellfish,
dried fruits or beans, peas, chocolate, cocoa, mushrooms, unprocessed wheat,
and nuts.
Is Wilson’s genetic? If so
what genes are involved with inherited forms of Wilson’s Disease?
Wilson’s disease is acquired through autosomal recessive inheritance,
creating a defect of cellular copper export. The defect is localized
on chromosome 13 and affects the copper transporting protein ATP7B in the liver.
Using ATP as an energy source, ATP7B transports copper at the N-terminal domain
across cellular membranes. A multitude of mutations can affect ATP7B. 10-40%
of patients are affected by the H1069Q mutation, the most common mutation identified
among Wilson’s patients. All mutations affect both the secretion
of copper into the biliary system as well as decreasing the incorporation of
copper into the apoceruloplasmin. Thus, a reduction in both formation and secretion
of ceruloplasmin as well as a reduction in copper elimination occurs.
What genetic counseling could you offer Wilson’s disease patients
and their family members?
“At risk relatives” are considered to be first-degree relatives
of a known individual with Wilson’s Disease. Screening of at risk individuals
should include: a physical examination, liver function tests, measurement of
serum copper, ceruloplasmin, and 24-hour urine copper excretion, as well as
slit-lamp examination. As a result of both the multiple mutations as well as
the multiple location sites across the genome, genetic testing within relatives
of individuals with Wilson’s has limited success in identifying mutations.
Before evaluation, a family member with known Wilson’s Disease should
first be tested to assess for a detectable mutation location. Testing identifies
patterns of di- and tri-nucleotide repeats around ATP7B. While mutation analysis
is not available in the United States, multiple labs perform haplotype analysis
(genetic linkage analysis) in families with at least two affected full siblings.
What diseases or medical problems does Wilson’s Disease place
a patient at increased risk?
- There are various studies that reveal different results as to whether Wilson’s
disease predisposes individuals to an increased risk of hepatocellular and
cholangiocarcinoma. The incidence of cancer is increased in relation to the
duration of time in which the patient has possessed the disease, with no increased
risk until having the disease for ten years.
What are the different variations of Wilson’s Disease?
- Menkes’ Disease- In this disease, there is a defect
in the transport of copper from the intestine. This defect leads to a deficiency
of copper that causes a severe progressive neurodegeneration ultimately leading
to death in patients with the disease. The disease is acquired by an x-linked
mode of inheritance.
Wilson’s Disease Patient Internet Resources:
- Wilson’s Disease Association International -http://www.wilsonsdisease.org/content_sub.asp?SUB_ID=57&CAT_ID=16
- Wilson’s
Disease Patient Fact Information-Wilson’s Disease
Patient Information Exchange -- www.gourmandizer.com/wilsons/indexx.html
RESOURCES:
- Thomas CR, Forbes JR, Roberts EA, et al. The Wilson Disease Gene: Spectrum
of Mutations and their consequences. Nat Genet 1995; 9:210.
- Steindl P, Ferenci P, Dienes HP, et al. Wilson’s Disease in Patients
Presenting with Liver Disease-A Diagnostic Challenge. Gastroenterology 1997;113:212.
- Jackson GH, Meyer A Lippmann S. Wlson’s Disease. Psychiatric Manifestations
May be the Clinical Manifestation. J Gastroenterol Hepatol 1992;4:370.
- Roberts, EA, Schilsky ML. AASLD guideline: A practice guideline on Wilson
Disease. Retrieved on August 19, 2006. www.uptodate.com
- Kaplan, MM. Diagnosis of Wilson’s Disease. Retrieved from UptoDate
on August 19, 2006. www.uptodate.com
- Kaplan, MM. Treatment of Wilson’s Disease. Retrieved from UptoDate
on August 19, 2006. www.uptodate.com
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